At Mayo Clinic, patient care and research are interdependent. Researchers and physicians translate discoveries from the research lab into innovative therapies for patients. Then, clinical studies evaluate such therapies and send data back to basic researchers for analysis, sometimes resulting in a new therapy. Final analysis may result in a new drug becoming publicly available, a new diagnostic test added to clinicians' toolboxes, or perhaps a trip back to the drawing board for the researchers.
The Women's Cancer Program has multidisciplinary teams of basic, clinical and population science investigators at Mayo's sites in Phoenix/Scottsdale, Ariz., Jacksonville, Fla., and Rochester, Minn., working together to advance understanding of cancers that uniquely affect women, and finding ways to lessen that burden. A brief overview of selected advances is listed below.
Letrozole Therapy Significantly Improves Long-term Outlook for Breast Cancer Survivors
An international clinical trial involving more than 5,000 women found that postmenopausal survivors of early stage breast cancer who took the drug letrozole after completing an initial five years of tamoxifen therapy had a significantly reduced risk of cancer recurrence compared to women taking a placebo.
While tamoxifen is widely used to prevent breast cancer recurrence in postmenopausal women, it loses effectiveness after five years because, researchers believe, tumors become resistant to it. Letrozole exerts an anti-estrogen effect in a different way. It limits the ability of an enzyme called aromatase to produce estrogen, a major growth stimulant in many breast cancers.
More than half of women who develop recurrent breast cancer do so more than five years after their original diagnosis. In the study, letrozole reduced the risk of breast cancer recurrence five years after diagnosis by 43 percent.
Based on the study, all postmenopausal women with hormone-receptor-positive tumors completing about five years of tamoxifen should discuss the advisability of taking letrozole with their doctors. Letrozole had a slight bone thinning effect, which means that women should have their bone mineral density monitored.
The form of the measles virus used in routine vaccination against measles infections has an interesting effect on cancer cells: it fuses several of them together into multi-cell "syncytia" that can no longer live. Because of this ability, the measles virus is currently undergoing Phase I clinical testing in ovarian cancer patients to see if intraperitoneal administration of the virus is safe. This version of the virus has been designed to also express a soluble protein called CEA that will allow researchers to measure whether measles virus replication is taking place in tumor cells.
Current studies focus on generating new versions of the measles virus that may be even more active against tumors. For example, the virus is being engineered to include the sodium iodide symporter (NIS) protein (Hasegawa et al. 2006) that functions to take up iodide molecules. Including NIS in this version of the measles virus would force the cancer cells to express NIS so that they could then be killed by administering radioactive iodine. Current studies focus on determining whether the NIS-measles virus could be used to fight ovarian cancer.
Mayo is the first institution to take up the study of an oncolytic measles virus, and in addition to an ovarian cancer clinical trial, has hope clinical trials exploring strains of measles virus to fight multiforme glioblastoma and multiple myeloma.
Reducing the Rate of Unnecessary Surgery and/or Re-operations for Breast Cancer
In early 2007, Mayo Clinic physician researchers reported at the 2007 Southwest Surgical Congress two studies that may allow hundreds of women to avoid unnecessary additional surgery for breast cancer. In the first study, the investigators, led by Dr. Gray, showed that women with microinvasive breast cancer (the earliest form of invasive breast cancer) who have spread of minimal cancer to their sentinel lymph nodes have a low risk of cancer being within additional lymph nodes. Thus these women may be able to avoid a complete removal of their armpit lymph nodes (complete axillary lymph node dissection). Because complete axillary lymph node dissection carries higher risks of lymphedema (arm swelling) and other side effects, avoiding this operation when safe can significantly improve breast cancer patients' quality of life.
The second study was of 204 women with nipple discharge. Most reports recommend that all such women undergo a surgical biopsy in order to rule out underlying cancer. But the Mayo Clinic study, also led by Dr. Gray, demonstrated that physicians can identify a large group of these patients who are at such low risk (less than 3 percent) of breast cancer being the cause of their discharge that they can be safely followed without an operation if they so choose. Avoiding the operative biopsy can avoid any possible side effects from the procedure and can also prevent scarring changes on mammograms.
In other efforts to reduce unnecessary extra surgeries, Dr. Gray and his fellow researchers have looked at ways to reduce the need for additional lumpectomies in women who have this cancer-removing procedure.
Because of increases in the use of mammography, the majority of women with breast cancer are now diagnosed before the cancer can be felt by doctors. Women undergoing a lumpectomy for these tumors must have the cancer marked by a localization device to allow the surgeon to find the cancer since it cannot be felt. The standard method, used for many years around the world, has been to insert a guide-wire through the woman's skin. Unfortunately, reports from surgeons using this method show that between 20-51 percent of women require a second operation because the cancer is too close to the edge of the removed tissue, risking that some cancer cells have been left in the remaining breast tissue.
Mayo Clinic researchers have reported the use of a new method for localizing breast tumors that can't be felt by the surgeon: radioactive seed localization. These investigators carried out a study that enrolled 400 breast cancer patients across the three Mayo Clinic campuses in Scottsdale/Phoenix, Ariz.; Jacksonville, Fla.; and Rochester, Minn.; that demonstrated radioactive seed localization lowered the rate of women requiring reoperation from 25 percent to 8 percent. These results confirm initial results from Mayo Clinic published in 2004. Mayo Clinic physicians are working with doctors at many hospitals around the country to assist them in instituting similar radioactive seed localization programs.
Recent data have shown that women who have detectable immune responses to their tumors tend to have better outcomes than women who do not have immune responses. Therefore, there is great interest in increasing tumor-specific immunity with the use of vaccines. In order to safely vaccinate women against ovarian tumors, researchers hope to identify target biomarkers that are abundant on the tumors, but are not highly expressed on other tissues in the body. Work at the Mayo Clinic has identified the folate receptor as a promising target for a vaccine approach.
The folate receptor is a protein that is expressed in most ovarian and breast tumors at levels much higher than found elsewhere in the body. Recent work has demonstrated that women with ovarian or breast cancer have generated immune responses against the folate receptor (Knutson et al. 2006). This study showed that lymphocytes and antibodies that recognize the folate receptor can be detected in the blood of women who have had ovarian or breast cancer at levels significantly higher than in women who have not had these diseases.
The long-term goal of this research team is to find ways to boost immunity to cancer cells after women have completed all treatment for their disease. A vaccine that activates the immune system to destroy any remaining microscopic cancer cells might delay or prevent the recurrence of the disease. The first step towards establishing immunotherapy approaches against cancer recurrence will be a Phase I clinical trial to evaluate the safety of a vaccine against the folate receptor. Currently pre-clinical studies are underway to gather data required by the U.S. Food and Drug Administration to test the vaccine in humans.
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